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Abstract The synthesis of a new type of Hoveyda–Grubbs 2nd generation catalyst bearing a modified N-heterocyclic carbene ligands is reported. The new catalyst contains an NHC ligand symmetrically substituted with chromanyl moieties. The complex was tested in model CM and RCM reactions. It showed very high activity in CM reactions with electron-deficient α,β-unsaturated compounds even at 0 °C. It was also examined in more demanding systems such as conjugated dienes and polyenes. The catalyst is stable, storable and easy to purify.

Introduction Olefin metathesis is still one of the most intensively studied transformations in synthetic organic chemistry. It has been frequently used as a key bond-forming reaction for total syntheses of many natural products [1]. The study on designing new metathesis catalysts and their synthesis has been a very fast developing area of organic chemistry since 1992, when Grubbs discovered the first well-defined ruthenium catalyst [2]. Nearly 400 ruthenium heterocyclic carbene-coordinated olefin metathesis catalysts were prepared until 2010 [3]. Since 2011, when Grubbs reported the synthesis of a Z-selective catalyst [4], several modified stereoselective catalysts were described [5-8]. Over the last few years, considerable attention has also been

paid to immobilisation and tagging of catalysts and especially on making them more environmentally friendly [9-14]. Alkene cross-metathesis (CM) is a convenient route to the synthesis of functionalised olefins from simple precursors. Since the discovery of Grubbs 2nd generation catalyst (1, Figure 1) [15], Hoveyda–Grubbs 2nd generation catalyst (2, Figure 1) [16] and some successful modifications, e.g., nitro-Grela catalyst (3, Figure 1) [17] the utility of CM has been continuously expanded. The synthesis of complex structures bearing polar functional groups can be accomplished by CM [18]. Grubbs et al. recognised that CM can be selective when two partners

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showing different reactivity are used, e.g., reactive terminal olefin (type I) and an electron-deficient olefin (e.g., acrylates or acrylonitriles, type II or III). In these cases, full conversion and high yields can be achieved [18]. Although the problem with the CM reactions of olefins with electron-withdrawing groups, such as α,β-unsaturated ketones and esters, is partly solved [19,20], the conditions of the reactions need some improvement (lower catalyst loading, lower temperature). To the best of our knowledge, there is no such type of reaction performed at 0 °C. A lower temperature of the reaction is important in the synthesis of unstable and thermally-sensitive natural products.

Figure 1: Examples of olefin metathesis ruthenium catalysts.

We previously reported a few catalysts bearing the chromanyl moiety, derived from vitamin E [21-23]. In such a system as 2,2,5,7,8-pentamethyl-6-hydroxychromane (α-tocopherol model compound) specific stereoelectronic effects are observed [24,25], which might improve the activity of the catalyst bearing the above-mentioned moieties. The ruthenium complexes 4–6 (Figure 2) that we reported earlier appeared to be the so-called dormant catalysts. Their activity in RCM reactions was low at room temperature and higher at elevated temperature [21]. In catalyst 7 the chelating oxygen atom was provided by the rigid heterocyclic ring of the chromenylmethylidene moiety, whereas in the Hoveyda–Grubbs 2 nd generation catalyst, the complexing oxygen atom comes from the freely rotating isopropoxy substituent. This complex proved to be quite efficient and showed activity comparable to that of commercially available catalysts 1 and 2 [23]. The introduction of a nitro group into the 6-position of the chromene moiety in catalyst 8 led to a decrease in the stability of the complex [22]. The aforementioned modifications concerned the benzylidene moiety of the catalysts and affected the initiation rate of the metathesis reaction. Changes in the NHC ligand are also very important because this part of the catalyst participates all along the metathetic process. As a result, the catalyst may gain new

properties, increased activity or stereoselectivity. Following this idea, we decided to synthesise a new catalyst bearing two chromanyl moieties symmetrically N,N’-disubstituted in the imidazolinium ring (9, Figure 2). According to Smith et al. [26] α-tocopherol and its amino analogue (α-tocopheramine) have comparable properties, coming from the same stereoelectronic effects mentioned above [24,25]. We expected that these effects may confer new properties of the NHC ligand.

Results and Discussion Synthesis of the carbene precursor The synthesis of an imidazolinium salt as a carbene precursor was started from 2,2,5,7,8-pentamethylchromane (10), which was prepared by the reaction between 2,3,5-trimethylphenol and 3-methylbut-2-enol [27]. Chromane 10 was nitrated with fuming nitric acid to give 6-nitrochromane 11 in 58% yield according to Mahdavian [28] (Scheme 1). Nitration using the Smith procedure [29] led to the expected nitrochromane 11, however, formation of an admixture of 5a,6-dinitrochromane was observed. Reduction of the nitro group in 11 was slightly troublesome, probably due to steric hindrance. The telluriumrongalit system was found to be the most efficient [30], and 6-chromanylamine 12 was obtained in 50% yield. Imidazolinium salt 14 was prepared according to the classical

protocol. Chromanylamine 12 was subjected to reaction with 2,3-dihydroxy-1,4-dioxane (glyoxal equivalent) followed by reduction of the intermediate diimines by NaBH3CN to give ethylenediamine 13 in 90% yield. Usage of the more convenient sodium borohydride led to a prolonged reaction time (up to 20 h) and a lower reaction yield. Imidazolinium salt 14 was obtained by treatment of 13 with trimethyl orthoformate in 73% yield. It is worth noting that ethylenediamine 13 and imidazolinium salt 14 were sufficiently pure after precipitation, thus chromatographic purification was not necessary. Some specific effects are observed in the NMR spectra of salt 14. In the 1H NMR spectrum, the signals from protons of the imidazolinium ring have atypical multiplicity. Two neighbouring triplets are also present besides the expected singlet from the ethylene bridge between the two nitrogen atoms symmetrically substituted by two identical chromenyl moieties. Similarly, the C-2 protons give two singlets instead of one. We suspected that there is a hindered rotation on the N–C(chromenyl) bond, so that two conformers are observed by NMR. However, the 1H NMR spectrum recorded at elevated temperatures (30 and 50 °C) looked the same. In the 13C NMR spectrum, signals from some of the carbon atoms are doubled. The HSQC correlation confirms that the doubled signals derive from one carbon atom. This fact also may suggest that two conformers are observed in the NMR spectra. This issue will be the subject of future detailed investigations.

Synthesis of the catalyst The new catalyst, 9, was obtained from imidazolinium salt 14 by deprotonation with potassium tert-amylate followed by the tricyclohexylphosphine ligand exchange in Hoveyda–Grubbs 1st

generation catalyst to give the target catalyst 9, which was purified on silica gel. The complex was stable in solid state at 0 °C for a few weeks (NMR test). Attempts to obtain a monocrystal that would be suitable for X-ray analysis failed. The 1H NMR spectrum confirmed the structure of the catalyst. In the 13 C NMR spectrum, some signals were broad and weak, e.g., signals of the quaternary aromatic carbon atoms and the primary carbon atoms of the methyl group attached to the aromatic ring of the chromanyl moieties. The HSQC correlation confirmed the structure of the catalyst and showed good correlation of the attached proton signals with the weak carbon peaks. When the 13C NMR spectrum is recorded at 50 °C, the spectrum becomes simpler but still many signals are almost invisible (at the noise level). The mass spectrum (HRMS) of 9 clearly evidences the molecular weight and the elemental composition of the new catalyst. The most likely unusual NMR spectra of 9 can result from specific stereoelectronic effects observed in the chromanyl system [24,25]. The 2p-type lone pair of electrons of the heterocyclic ring oxygen atom adopts an orientation almost perpendicular to the plane of the aromatic ring allowing for an electronic interaction with the para-substituent of the chromanyl system (–OH in 6-hydroxychroman and –NH2 in 6-aminochroman).

Testing of the new catalyst The catalyst proved very active in model cross-metathesis reactions, especially with olefins containing electron-withdrawing groups. For example the reaction of allylbenzene and ethyl acrylate at room temperature was almost quantitative. These results prompted us to test this reaction at a lower temperature (0 °C). Commercially available catalysts 1 and 2 proved inac-

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tive under these conditions, therefore we compared our catalyst with Grela catalyst 3 [17]. As is shown in Table 1 (entry 1), both catalysts, i.e., 3 and 9 proved very active. After reduction of the catalyst loading to 1 mol %, the yields of the ethyl acrylate reaction with allylbenzene catalysed by both complexes 3 and 9 were still very good (close to 80%, Table 1, entry 2). Encouraged by these results, we decided to test 9 in a CM reaction with other α,β-unsaturated compounds, e.g., methyl vinyl ketone (entry 3, Table 1) and acrylonitrile (entry 4, Table 1). The outcome of these reactions was also very promising for 9. It should be added that in all cases a dimer of the electron-deficient olefin was not observed. The homodimerisation product of allylbenzene (entries 1 and 2, Table 1) was formed in less than 10% (in case of the reaction catalysed by 2 no dimeric products were observed), while the yield of the homodimer of hex-5-enyl acetate (entries 3 and 4, Table 1) was below 3%. Low conversion (especially that obtained with 1 and 2) was related to substantial amounts of unreacted substrates. The high activity of Grela catalyst 3 was a result of faster initiation of the catalytic cycle arising from the electron-withdrawing effect of the nitro group. Consequently, lowered electron density at the oxygen atom in the isopropoxybenzylidene fragment weakens the coordination to the ruthenium atom, and finally, facilitates the initiating process. In the new catalyst 9, which is modified in the NHC ligand, different effects are responsible for its activity. According to Grubbs [31], catalyst 1 is able to react with α,β-unsaturated carbonyl compounds to form an enoic carbene [Ru]=CHCOX, which is kinetically favourable. As a result, a stronger electron-donating ligand should stabilise the electron-deficient enoic carbene [31]. One can speculate that specific stereoelectronic effects occurring in

the chromanyl system, known from the vitamin E chemistry, contribute to high activity of 9. The N-(2,2,5,7,8-pentamethyl-6chromanyl) substituents, bearing electron releasing methyl groups as well as interplaying dihydropyranyl oxygen and nitrogen atoms in the imidazolidine cycle, can stabilise the enoic carbene (Scheme 2).

Scheme 2: CM with electron-deficient olefin.

The CM products of terminal olefins (entries 1–3, Table 2) were obtained in high and very high yields. Alkenes were converted almost quantitatively and the excess of (Z)-but-2-ene-1,4-diol diacetate was recovered. Some side products of self-metathesis (SM) of terminal alkenes were isolated. It should be added that two terminal olefins (entry 4, Table 2) gave also SM products besides the desired CM products. Furthermore, more dimeric products gave allyloxybenzene than hex-5-enyl acetate. It is worth noting that the CM reaction between styrene and (Z)-but-

2-ene-1,4-diol diacetate (entry 1, Table 2) was highly efficient (97% yield) using catalyst 9. Moreover, in the CM of allyloxybenzene and hex-5-enyl acetate, the yield with 9 was almost twice higher than that obtained for 1 or 2 (entry 4, Table 2). In the model RCM, the activity of catalyst 9 was slightly lower than that of commercial complexes, supposedly due to steric reasons (Table 3). The potency of the new catalyst 9 was tested not only in standard, model metathesis reactions but was also examined in more demanding systems, such as conjugated dienes and polyenes (Table 4). The CM reaction between alkene and diene (or polyene) often suffers from low regio- and stereoselectivity control. The CM reaction may be accompanied by various selfmetathesis processes. Additionally, due to the competitive cleavage of both double bonds of the diene substrate, two different products may be formed in the CM reaction between

alkene and diene (Scheme 3). A further complication is a Z/E isomer mixture formation. The reactions of ethyl sorbate and its 3-methyl substituted analogue (ethyl (2E,4Z/E)-3-methylhexa-2,4-dienoate) with various alkenes were chosen to examine the activity and selectivity profile of catalyst 9 (Table 4). The results clearly indicate that carbene 9 can promote the CM reactions of dienes with different olefins as efficiently as commercial Grubbs 2nd generation and Hoveyda–Grubbs 2nd generation complexes 1 and 2. Complex 9 catalysed the reactions of ethyl 3-methylhexa-2,4dienoate in a completely selective manner taking into account product regio- and stereoselectivity. In all reactions the E-isomer of compound A was formed as a main product (Table 4, entries 1–3). Homodimerisation products of diene and alkene were obtained in very small amounts (